The availability of genetically modified mice has advanced our understanding of Alzheimer's disease (AD). Nevertheless, conventional tools of cellular neurobiology, which require the sacrifice of an animal to obtain information about neuronal function, preclude the use of longitudinal study designs. Functional Magnetic Resonance Imaging (fMRI) is a technology that can obtain information about the metabolic state of the brain non-invasively and thus allows the use of longitudinal study designs in both rodents and humans. Some fMRI protocols, such as those designed to measure cerebral blood volume (CBV), are especially sensitive to long term metabolic changes in the brain caused by neurodegenerative disease. Mounting evidence suggests that calcium-binding proteins (CaBPs) play a role in Alzheimer's disease (AD). In this proposal, the technologies of fMRI and transgenic engineering will be combined to accomplish the following primary goals: First, to acquire expertise in mouse fMRI as it specifically applies to AD research. Second, to rely on mouse fMRI to investigate the role calcium-binding proteins play in AD pathophysiology. This goal will be achieved by crossing mouse models of AD with transgenic mice in whom calcium-binding proteins have been manipulated, and then by imaging these mice prospectively over time. As a secondary goal, in vitro techniques will be used to confirm and extend the in vivo findings. These experiments will test the specific single cell calcium abnormalities in different cellular compartments of the hippocampal formation. The training aspects of this proposal will lead to a new investigator in the field of AD research with combined expertise in clinical neurology and mouse fMRI. The scientific aspects of this proposal will test a specific mechanism regarding AD pathophysiology, which might inform future therapeutic goals. It is also important to emphasize that advances in mouse fMRI can be easily applied to humans, e.g. evaluation of the response to a given treatment by brain fMRI parameters.